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Discovery and Optimization of Narrow Spectrum Inhibitors of Tousled Like Kinase 2 (TLK2) Using Quantitative Structure Activity Relationships.

ABSTRACT: The oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was a potent off-target kinase. The oxindole has long been considered a promiscuous inhibitor template, but across these 4 specific literature oxindoles TLK2 activity was consistent, while the kinome profile was radically different from narrow to broad spectrum coverage. We synthesized a large series of analogues and through quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites, small-molecule x-ray structural analysis and kinome profiling, narrow spectrum, sub-family selective, chemical tool compounds were identified to enable elucidation of TLK2 biology.

SUBMITTER: Asquith CRM

PROVIDER: S-EPMC10793458 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Discovery and Optimization of Narrow Spectrum Inhibitors of Tousled Like Kinase 2 (TLK2) Using Quantitative Structure Activity Relationships.

Asquith Christopher R M CRM East Michael P MP Laitinen Tuomo T Alamillo-Ferrer Carla C Hartikainen Erkka E Wells Carrow I CI Axtman Alison D AD Drewry David H DH Tizzard Graham J GJ Poso Antti A Willson Timothy M TM Johnson Gary L GL

bioRxiv : the preprint server for biology 20231228

The oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was a potent off-target kinase. The oxindole has long been considered a promiscuous inhibitor template, but across these 4 specific literature oxindoles TLK2 activity was consistent, while the kinome profile was radically different from narrow to broad spectrum coverage. We synthesi ...[more]

PMID: 38234837

Dataset Information

Discovery and Optimization of Narrow Spectrum Inhibitors of Tousled Like Kinase 2 (TLK2) Using Quantitative Structure Activity Relationships.

Publications

Discovery and Optimization of Narrow Spectrum Inhibitors of Tousled Like Kinase 2 (TLK2) Using Quantitative Structure Activity Relationships.

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